The present invention relates to improved medical procedures involving hemodilution. The improved method includes the administration of an oxygen carrier, the continuous monitoring of the mixed venous partial pressure of oxygen (PvO2) or other tissue oxygenation indices, and the administration of autologous blood or additional oxygen carrier to maintain the PvO2 or other indices at or above a predetermined level.
More than 13 million units of blood are collected each year in the United States alone, and about 10 million of these units are transfused into 4 million recipients. Of the transfused units, about two-thirds are used during surgical procedures, and the remainder are used primarily for treating severe anemia or in emergency indications. Experience from clinical studies suggests that postoperative recovery can be shortened if hemoglobin concentrations are not allowed to fall to below 10 g/dL, the previously generally accepted indication for transfusion (Zauder, Anesth. Clin. North Amer. 8:471-80 (1990)). This criterion, however, is currently being reevaluated due in part to a recent increase in awareness of the risks associated with allogeneic blood transfusion (NIH Consensus Conference JAMA 260:2700-2703 (1988)). This has also resulted in a renewed interest in the use of autologous blood transfusion techniques, in particular predonation and cute normovolemic hemodilution (ANH).
Although autologous blood transfusion (i.e., reinfusion of the patient""s own blood) was first employed over 170 years ago, it was not until the early 1970s that its use became more widespread because of growing concerns about the transmission of hepatitis. More recently, interest in autologous transfusions on the part of both patients and physicians has been stimulated by the emergence of AIDS. Despite an increased awareness and acceptance of the benefits of autologous blood transfusion, recent studies have revealed the widespread underutilization of autologous predonation (which is estimated to represent only 2-5% of all units drawn nationwide).
ANH is a procedure whereby several units of blood are withdrawn from the patient at the beginning of surgery and simultaneously replaced with either a crystalloid or a colloid plasma volume expander (Stehling et al. Transfusion 31:857 (1991)). The basic mechanism that compensates for most of the decreased oxygen capacity of the diluted blood is the rise in cardiac output and increased organ blood flow, factors that result from the improved fluidity of blood (i.e., lower viscosity) at lower hematocrit levels (Messmer et al Eur. Surg. Res. 18:254-263 (1986)). Weisskopf, Transfusion 35(1):37-41 (1995) describes a mathematical analysis of acute isovolemic hemodilution prior to surgical blood loss, which was used to determine the magnitude of potential reductions in allogeneic transfusion. Weisskopf concluded that isovolemic hemodilution prior to surgery can obviate allogeneic blood transfusion or diminish the amount transfused.
Predonation typically involves withdrawal of several units of a patient""s blood during the six weeks prior to surgery. To avoid excessive anemia, the amount of blood that can be safely predonated in the weeks before surgery is limited, as is the amount of blood that can be removed during ANH.
Quite apart from ANH and predonation, it has been suggested that red cell substitutes, or blood substitutes, could be used in place of allogeneic blood (i.e., blood from other humans) during surgery. Methods for facilitating autologous blood use which employ a synthetic oxygen carrier or blood substitute are disclosed in U.S. Pat. No. 5,344,393 (Roth et al). Extensive research in the field of such blood substitutes over the past two decades has resulted in several candidate compositions. These include perfluorocarbon emulsions, such as FLUOSOL (Green Cross Corporation, Japan) and OXYGENT (Alliance Pharmaceutical Corp., San Diego, USA), and hemoglobin compositions, such as those derived from human, animal, or recombinant sources.
Traditional thinking has been that a red cell substitute would be given in volumes equal to the amount of whole blood that would be used for the same purpose. The use of such blood substitutes in large volumes to replace blood used in transfusions has not been entirely satisfactory in earlier applications. For example, early studies using FLUOSOL as a large volume blood substitute found that following blood loss, FLUOSOL was xe2x80x9cunnecessary in moderate anemia and ineffective in sever anemia.xe2x80x9d Gould, et al., New Engl. J. Med. 314:1653 (1986). In this study, the average increase in arterial oxygen content with the drug was only 0.7 ml/deciliter. Thus, it was concluded that use of fluorocarbon emulsions as blood substitutes would not provide a significant benefit in severely anemic and bleeding patients. Indeed, although the U.S. Food and Drug Administration approved FLUOSOL in 1989 for use as a perfusion agent to enhance myocardial oxygenation during percutaneous transluminal coronary angioplasty (PTCA), it did not approve an earlier application for use as a large volume blood substitute for general use.
The problem in using fluorocarbon emulsions and hemoglobin compositions as red cell substituted or blood substitutes to compensate for blood loss from surgery, disease, or trauma lies in the relatively short circulating blood half life of those materials in vivo. Healthy humans typically require about two weeks to manufacture new red cells and increase their hematocrit to normal levels following blood loss. In contrast, the intravascular half life of fluorocarbon emulsions and hemoglobin substitutes in vivo is typically less than 72 hours, most often much less than 24 hours. Thus, even if sufficient quantities of a red cell substitute are administered during and/or after surgery, for example, to provide adequate oxygen delivery, the oxygen carrying capacity will drop significantly long before the body can compensate by making new red cells. One aspect of the current invention therefore defines an improved method to use red cell substitutes or blood substitutes for temporary short-time perioperative use in conjunction with autologous blood conservation strategies as a means of reducing or eliminating allogeneic blood transfusions.
Treatment of intracoronary thrombotic events such as myocardial infarcts usually involves systemic administration of thrombolytic agents, for example tissue plasminogen activator (tPA) or streptokinase. Mechanical intervention using percutaneous coronary angioplasty (PTCA) is also used. Under no circumstance during current treatment methods is blood purposefully diluted, as this would dilute the concentration of red blood cells and thus impair the delivery of oxygen to the hearts. Many cellular elements of blood, however, are detrimental in the case of myocardial infarction. For example, it is well known that platelets are necessary for the process of thrombus formation; reduction in the number of platelets would result in attenuation of the rate of thrombus formation following infarction. Further, certain white blood cells, polymorphonuclear leukocytes (neutrophils), are known to be activated at the site of the infarct to release cytotoxic components including oxygen free radicals, which, upon successful opening of the stenosed artery, are responsible for damaging normal cells through a phenomenon known as reperfusion injury. It would be beneficial, therefore, to dilute blood during and for a specified time after treatment of a myocardial infarction in order to reduce the number of platelets and neutrophils that exacerbate the effects of the infarct. Hemodilution is not done, however, because it is also necessary to maintain high red blood-cell levels to deliver oxygen to the myocardium.
The current invention therefore also defines an improved method to use red cell substitutes or blood substitutes for temporary short-term use in conjunction with treatment of myocardial infarction as a means of reducing or eliminating the detrimental effects associated with the infarct while providing enhanced oxygen delivery to the tissues.
The present invention provides a method for facilitating autologous blood use by a patient facing a loss of blood, comprising the steps of: removing and storing a portion of the patient""s blood while intravenously administering a biocompatible liquid in sufficient quantity to bring the patient""s blood hemoglobin level to a desired concentration; intravenously administering a biocompatible oxygen carrier, while periodically or continuously assessing the patient""s tissue oxygenation, after which the patient undergoes a further loss of blood; and intravenously readministering the stored blood to the patient in response to the oxygenation measurements to maintain oxygenation measurements at or above a desired value. In one embodiment, the biocompatible liquid comprises a hemodiluent. In another embodiment, the hemodiluent is administered separately from the oxygen carrier. The method further comprises the step of administering additional oxygen carrier in response to the oxygenation assessments to maintain oxygenation assessments at or above a desired value prior to readministering the stored blood. The oxygen carrier is preferably derived from human, animal, plant, or recombinant hemoglobin, or it may be a fluorocarbon emulsion.
When the oxygen carrier is a fluorocarbon emulsion, the volume of the administered oxygen carrier is advantageously less than 50% of the volume of the biocompatible liquid. The fluorocarbon emulsion preferably has a concentration of at least 40%, preferably 50% or 60% w/v.
The biocompatible liquid is advantageously selected from the group consisting of a crystalloid, a colloid, a biocompatible oxygen carrier, and combinations thereof. The method also may further comprise the step of administering oxygen breathing gas to the patient during the procedure. The blood loss is often blood loss associated with surgery. Alternatively, the blood loss is associated with trauma.
The amount of oxygen carrier administered is usually between about 0.5 and 10 ml/kg, based on the body weight of the patient. The desired concentration of hemoglobin may advantageously be about 8 g/dL. The assessing of the patient""s tissue oxygenation can be performed by assessing PvO2, such as by using a pulmonary artery catheter. Preferably, the desired value of PvO2 referred to above is about 40 mmHg.
The present invention also includes a method for the treatment of organ ischemia or infarct, including myocardial infarction, comprising the steps of removing a portion of the blood of a patient in need of treatment for organ ischemia or infarct and intravenously administering a biocompatible liquid in sufficient quantity to reduce the patient""s blood hemoglobin level to a desired concentration; and intravenously administering a biocompatible non-red cell oxygen carrier in conjunction with the removing step to maintain oxygenation of the patient""s tissues at or above a predetermined level. In one embodiment, the biocompatible liquid comprises a hemodiluent. In another embodiment, the hemodiluent is administered separately from the oxygen carrier. The oxygen carrier and biocompatible liquid may be the same or different, and may be as described above. The method advantageously also includes the step of administering oxygen breathing gas to the patient during the method. The amount of oxygen carrier administered is preferably between about 0.5 and 10 ml/kg, based on the body weight of the patient. As above, one preferred concentration of hemoglobin after hemodilution is about 8 g/dL. In order to assure adequate oxygenation of tissue including myocardium, the method further comprises the step of assessing the patient""s tissue oxygenation by assessing PvO2, as discussed above, to maintain a desired value of PvO2 at a value, for example, of about 40 mmHg. In one modification of the method, the oxygen carrier constitutes at least a part of the biocompatible liquid.
In addition to the foregoing, the invention comprises a method of hemodiluting a patient, comprising the steps of removing and storing a portion of the patient""s blood while intravenously administering a biocompatible oxygen carrier and periodically or continuously assessing the patient""s tissue oxygenation, after which the patient undergoes a further loss of blood, and administering additional oxygen carrier to the patient in response to the oxygenation assessments to maintain the oxygenation assessments at or above a desired value. The method may further comprise the step of readministering the stored blood to the patient. The oxygen carrier and the desired values of oxygen carrier delivery and oxygenation may be as described above. The method may also include the step of administering oxygen breathing gas to the patient during the method.
Yet another aspect of the present invention comprises a method of hemodiluting a patient, comprising the steps of removing and storing a portion of the patient""s blood while intravenously administering a biocompatible oxygen carrier and periodically or continuously assessing the patient""s tissue oxygenation, after which the patient undergoes a further loss of blood. The method may further comprise the step of readministering the stored blood to said patient. The oxygen carrier and the desired values of oxygen carrier delivery and oxygenation may be as described above. The method may also include the step of administering oxygen breathing gas to the patient during the method.